Cold Chain-Independent, Needle-Free Mucosal Virosomal Vaccine to Prevent HIV-1 Acquisition at Mucosal Levels

不依赖冷链、无针粘膜病毒体疫苗，可预防粘膜水平的 HIV-1 感染

• 批准号: 10401878
• 负责人: Sylvain FLEURY
• 金额: $ 161.59万
• 依托单位: UNIVERSITY OF LOUISIANA AT LAFAYETTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10401878
• 关键词: AIDS Vaccines; Acquired Immunodeficiency Syndrome; Address; Adjuvant; Affect; Animal Model; Animals; Antibodies; Antibody Response; Biomedical Research; Chinese; Clinic; Clinical; Cold Chains; Collaborations; Data; Development Plans; Dosage Forms; Dose; Double-Blind Method; Epidemic; Experimental Designs; Female; Formulation; HIV; HIV Envelope Protein gp41; HIV Vaccine Trials Network; HIV vaccine; HIV-1; Human; Immunization; Immunoglobulin A; Immunoglobulin G; Influenza; Intramuscular; Invaded; Lead; Link; Liquid substance; Macaca mulatta; Membrane; Mucous Membrane; Needles; Nose; Oral; Peptides; Phase; Phase I Clinical Trials; Pilot Projects; Plasma; Powder dose form; Program Development; Publishing; Recombinants; Refrigeration; Reporting; Research Institute; Route; SIV; Safety; Solid; Surface; Systemic infection; TLR7 gene; Tablets; Texas; Time; Toxicology; Vaccinated; Vaccination; Vaccinee; Vaccines; Viremia; Virion; Virosomes; Virus-like particle; Woman; antibody-dependent cell cytotoxicity; base; capsule; design; human male; immunogenic; immunogenicity; improved; male; manufacturing process; neutralizing antibody; nonhuman primate; novel; novel vaccines; particle; phase I trial; pre-clinical; prevent; response; seroconversion; sexual HIV transmission; simian human immunodeficiency virus; transcytosis; transmission process; vaccine candidate; vaccine delivery; vaccine development; vaginal fluid; virus envelope; ward

PROJECT SUMMARY – OVERALL This multi-PI application is a collaboration between Mymetics and the Texas Biomedical Research Institute (TxBiomed), with Drs. Sylvain Fleury (Project 1 Lead; Mymetics) and Ruth Ruprecht (Project 2 Lead; TxBiomed) serving as PIs. We seek to bring a promising HIV/AIDS vaccine approach to the clinic. The vaccine is based upon influenza virosomes, enveloped virus-like particles that display on their surface elongated HIV gp41 peptides (virosome-P1) or recombinant truncated HIV gp41 (virosome-rgp41). Mymetics' Phase I clinical trial with virosome-P1 in healthy women showed safety and immunogenicity. Two independent nonhuman primate (NHP) studies demonstrated the safety and high efficacy of the combination of virosome-P1 + virosome rgp41 against repeated low-dose intravaginal challenges with a tier 2 R5 SHIV in Chinese and Indian-origin rhesus macaques (RMs). In the latter, 78-87% efficacy was noted when the SHIV challenge dose was ~7x104 times the median HIV inoculum in male-to-female HIV transmission. However, when this HIV inoculum was exceeded 105- fold by an even higher SHIV inoculum, protection in Indian RMs was lost, implying a threshold effect whereby vaccine-induced mucosal antibodies were unable to ward off the higher number of invading SHIV particles. The soluble vaccine used in both NHP studies was unadjuvanted. To improve immunogenicity, Mymetics has embedded the toll-like receptor (TLR)7/8 adjuvant 3M-052 into virosomal envelopes. Moreover, Mymetics has developed a powdered form of virosomes that is no longer cold-chain dependent and can be administered as intranasal (IN) spray, sublingual (SL) tablets, or packaged into oral capsules. We hypothesize that these novel solid virosome formulations are significantly more immunogenic, particularly when administered via mucosal routes, than the unadjuvanted liquid form used earlier in NHPs. The Specific Aims of this IPCAVD project are to: 1. Assess the immunogenicity of the new vaccine candidates, the newly 3M-052-adjuvanted HIV virosome-P1 and virosome-rgp41, under solid dosage forms delivered IN, SL, or orally to Indian RMs in order to select the two most immunogenic formulations for subsequent mucosal prime/mucosal boost immunization. 2. Assess the efficacy of the cold-chain independent virosomal vaccine delivered by combined mucosal immunization routes against repeated intrarectal challenges with the heterologous R5 clade B SHIVSF162P3. Protected RMs will be rechallenged with an R5 tier 2 clade C SHIV. 3. Optimize the GMP manufacturing process for the selected virosomal formulations for mucosal delivery, and 4. Perform toxicology studies to show good safety profiles of the adjuvanted, solid-form vaccines given by selected mucosal routes – and generate GMP vaccine for a Phase I trial to be conducted with the HVTN. Our vaccine development plans represent major advances, as the novel needle-free, solid vaccine dosage forms are cold-chain independent and will be mucosally delivered – unique aspects that make the novel virosomal vaccines especially attractive for the developing world, where the AIDS epidemic remains a serious problem.

项目概要——总体 这个多 PI 应用程序是 Mymetics 和德克萨斯生物医学研究所之间的合作 （TxBiomed），与博士。 Sylvain Fleury（项目 1 负责人；Mymetics）和 Ruth Ruprecht（项目 2 负责人；TxBiomed） 担任 PI。我们寻求将一种有前景的艾滋病毒/艾滋病疫苗方法引入临床。该疫苗是基于 在流感病毒体上，有包膜的病毒样颗粒在其表面展示延长的 HIV gp41 肽（病毒体-P1）或重组截短的HIV gp41（病毒体-rgp41）。 Mymetics 的 I 期临床试验 病毒体-P1在健康女性中显示出安全性和免疫原性。两只独立的非人类灵长类动物 (NHP) 研究证明病毒体-P1 + 病毒体 rgp41 组合的安全性和高效性 对抗来自中国和印度的恒河猴反复进行低剂量阴道内 2 级 R5 SHIV 攻击 猕猴（RM）。在后者中，当 SHIV 攻击剂量约为 7x104 倍时，效率为 78-87%。 男性向女性艾滋病毒传播中艾滋病毒接种量的中位数。然而，当 HIV 接种量超过 105- 由于 SHIV 接种量更高，印度 RM 的保护作用消失了，这意味着阈值效应，即 疫苗诱导的粘膜抗体无法抵御大量入侵的 SHIV 颗粒。这 两项 NHP 研究中使用的可溶性疫苗均未添加佐剂。为了提高免疫原性，Mymetics 将 Toll 样受体 (TLR)7/8 佐剂 3M-052 嵌入病毒体包膜中。此外，Mymetics 还 开发了一种粉末形式的病毒体，它不再依赖于冷链，并且可以作为 鼻内 (IN) 喷雾剂、舌下 (SL) 片剂或包装成口服胶囊。我们假设这些小说 固体病毒颗粒制剂的免疫原性明显更高，特别是通过粘膜给药时 途径，而不是早期在 NHP 中使用的无佐剂液体形式。该 IPCVD 项目的具体目标是： 1. 评估新候选疫苗（新的 3M-052 佐剂 HIV 病毒颗粒-P1）的免疫原性 和病毒体-rgp41，以固体剂型以 IN、SL 或口服方式递送给印度 RM，以便选择 两种最具免疫原性的制剂，用于随后的粘膜初免/粘膜加强免疫。 2. 评估联合粘膜递送的冷链独立病毒体疫苗的功效 针对异源 R5 进化枝 B SHIVSF162P3 反复直肠内攻击的免疫途径。 受保护的 RM 将接受 R5 2 级 C 分支 SHIV 的重新挑战。 3. 优化用于粘膜递送的选定病毒体制剂的 GMP 生产工艺，以及 4. 进行毒理学研究，以显示佐剂固体疫苗的良好安全性。 选择粘膜途径，并生成 GMP 疫苗，用于与 HVTN 进行的 I 期试验。 我们的疫苗开发计划代表了重大进步，因为新型无针固体疫苗剂型 不依赖于冷链，并且将通过粘膜递送——独特的方面使得新型病毒体 疫苗对发展中国家尤其有吸引力，因为艾滋病在这些国家的流行仍然是一个严重的问题。